Pursuant to our discovery (1971) of a photochemical method for the synthesis of fluoroimidazoles, we have shown that fluoro analogs of various bioimidazoles (histamine, histidine, etc.) possess a variety of valuable properties as biological substrates and inhibitors. 2-Fluorohistidine, for example, not only is incorporated into bacterial and animal protein in place of histidine, but also serves as an antibacterial, antiviral and antileukemic agent. Such results provided an impetus to develop synthetic methods for other new analogs of histamine and histidine with substituents at C-2, C-4 or both. We now have in hand analogs containing halogen, amino, formyl, cyano, nitro, ester, azido and trifluoromethyl groups. The azido analogs may be useful for photoaffinity labeling of receptors and enzymes. The trifluoromethyl analogs are especially interesting, since they are labile in mildly alkaline media and may serve as receptor affinity labels for use in vivo. Toward this end, the isomeric trifluoromethyl-His analogs of TRH have been synthesized and are undergoing biological evaluation. A surprising result is that 2-CF3-His-TRH fails to bind to rat pituitary cells in vitro and fails to release prolactin in this system. In vivo, however, the compound does promote prolactin release, suggesting that the brain contains nonpituitay receptors for TRH which also stimulate prolactin release. A computer analysis of electronic effects provided the prediction that imidazoles containing both fluoro and trifluoromethyl groups would have the necessary reactivity to serve as potential affinity labels under physiological conditions. We have recently developed techniques for the sequential introduction of both substituents into imidazoles, have verified the computer-based predictions of reactivity, and are now involved in the synthesis of peptide hormones containing these functional groups. Exposure of 4-trifluoromethylhistamine or histidine to mild base or ammonia results in facile cyclization to deaza analogs of purines. Several compounds in this series have recently been found to have potent antiviral properties and our analogs are now being tested. Deoxy derivatives of these compounds are being incorporated into peptide hormones as rigid cyclic analogs of histidine.